Cancer is the second leading cause of death in the United States. Although “cancer” is used to describe many different types of cancer, i.e. breast, prostate, lung, colon, pancreas, each type of cancer differs both at the phenotypic level and the genetic level. The unregulated growth characteristic of cancer occurs when one or more genes acquire mutations and cell growth can no longer be controlled.
Genes are often classified in two classes, oncogenes and tumor suppressor genes. Oncogenes are genes whose normal function is to promote cell growth, but only under specific conditions. When an oncogene gains a mutation and then loses that control, it promotes growth under all conditions. However, it has been found that for cancer to be truly successful the cancer must also acquire mutations in tumor suppressor genes. The normal function of tumor suppressor genes is to stop cellular growth. Examples of tumor suppressors include p53, p16, p21, and APC, all of which, when acting normally, stop a cell from dividing and growing uncontrollably. When a tumor suppressor is mutated or lost, that brake on cellular growth is also lost, allowing cells to now grow without restraints.
Although several genes and their protein products have been identified as being involved in tumorigenesis, the genes that play a role in metastasis are still unclear. Metastasis is an important part of tumorigenesis and is the spreading of the cancer from its primary site of growth to secondary sites that lead to the death of an individual. Examples of types of cancers that often spread to different areas of the body are prostate, breast, lung, and colon.
Most patients originally diagnosed with either prostate or breast cancer develop bone metastases and, at the time of death, most of the tumor burden is found in bone. Cancer has a wide range of bone-related effects. In metastases from breast cancer or from myeloma, the bone-related effect is typically osteoclastic. In contrast, metastases from prostate cancer typically cause osteoblastic effects. Skeletal related events (SREs) are often a result of bone metastases and lead to complications including bone pain, hypercalcemia, pathologic fractures, leukoerythroblastic anemia, bone deformity, and nerve-compression syndrome, among others, thought to be a result of osteolysis. (G. Mundy, Nature (2002), Vol. 2, 584-593). Median survival for patients with metastases to bone is between 2-3 years.
There is some evidence that inhibitors of bone resorption might be useful in inhibiting such complications. Bisphosphonates, pyrophosphate analogs used to treat diseases characterized by bone loss including osteoporosis and Paget's disease, cause a reduction in osteolytic bone lesions as well as a decrease in bone tumor burden. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 2nd Edition, Parthenon Publishing (1995), which is incorporated by reference herein in its entirety.
A great amount of preclinical and clinical data exists for the bisphosphonate compound alendronate. Evidence suggests that other bisphosphonates including tiludronate, ibandronate, risedronate and zolendronate, have many properties in common with alendronate, including high potency as inhibitors of osteoclastic bone resorption. An older bisphosphonate compound, etidronate, also inhibits bone resorption. There is speculation that existing therapies for inhibiting osteoclastic bone resorption may be effective in treating osteoblastic metastases if the osteoblastic response was dependent on a previous osteoblast activity. Other existing therapies for bone metastases include osteoprotegrin (thought to prevent RANK-L from binding to its receptor and stimulating osteoclasts), RANK-Fc (thought to prevent RANK-L from binding to its receptor and stimulating osteoclasts), PTHrP antibodies, and Vitamin-D analogs (thought to decrease PTHrP production). (G. Mundy, Nature (2002), Vol. 2, 584-593).
Although some studies support the contention that bisphosphonates reduce tumor burden in bone, there is controversy as to whether such inhibitors have the same effect in soft-tissue metastases. Indeed, one study reported that bisphosphonates actually promoted soft-tissue metastasis. (Saarto et al., J. Clin. Oncol. (2001), 19: 10-17).
Several molecules have been shown to be expressed in epithelial cell cancers including breast and prostate cancer. Although EphA2 has been previously shown to participate in oncogenic behavior in breast cancer cells, there are no published reports of a functional role of EphA2 in metastases of cancer to the bone, or in Skeletal Related Events (SREs).
Thus, there is a need to identify genes and gene products that play a role in cancer as well as in cancer metastases and in skeletal related events as well as models of metastasis and SREs. Similarly, there is a need to identify modulators of skeletal related events and metastasis as well as methods for modulating skeletal related events and metastasis. There is a further need to identify methods of imaging/detecting/diagnosing metastases and skeletal related events. The present invention is directed to these, as well as other, important needs.